Subinhibitory Concentrations of Antibiotics Alter the Response of Klebsiella pneumoniae to Components of Innate Host Defense

Carbapenem-resistant Klebsiella pneumoniae isolates classified as multilocus sequence type 258 (ST258) are a problem in health care settings in many countries globally. ST258 isolates are resistant to multiple classes of antibiotics and can cause life-threatening infections, such as pneumonia and sepsis, in susceptible individuals. Treatment strategies for such infections are limited. Understanding the response of K. pneumoniae to host factors in the presence of antibiotics could reveal mechanisms employed by the pathogen to evade killing in the susceptible host, as well as inform treatment of infections. Here, we investigated the ability of antibiotics at subinhibitory concentrations to alter K. pneumoniae capsular polysaccharide (CPS) production and survival in normal human serum (NHS). Unexpectedly, pretreatment with some of the antibiotics tested enhanced ST258 survival in NHS. For example, a subinhibitory concentration of mupirocin increased survival for 7 of 10 clinical isolates evaluated and there was increased cell-associated CPS for 3 of these isolates compared with untreated controls. Additionally, mupirocin pretreatment caused concomitant reduction in the deposition of the serum complement protein C5b-9 on the surface of these three isolates. Transcriptome analyses with a selected ST258 isolate (34446) indicated that genes implicated in the stringent response and/or serum resistance were upregulated following mupirocin treatment and/or culture in NHS. In conclusion, mupirocin and/or human serum causes changes in the K. pneumoniae transcriptome that likely contribute to the observed decrease in serum susceptibility via a multifactorial process. Whether these responses can be extended more broadly and thus impact clinical outcome in the human host merits further investigation.

Automated summary

Carbapenem-resistant Klebsiella pneumoniae isolates, specifically multilocus sequence type 258 (ST258), have developed resistance to multiple classes of antibiotics and can cause severe infections in susceptible individuals. This study investigates the impact of subinhibitory concentrations of antibiotics on the capsule production and survival of K. pneumoniae in normal human serum (NHS). Surprisingly, certain antibiotics, such as mupirocin, enhanced the survival of ST258 isolates in NHS and also increased the production of capsular polysaccharide (CPS). Further analyses revealed that mupirocin treatment and/or culture in NHS upregulated genes related to the stringent response and serum resistance in ST258 isolates. These findings suggest that the response of K. pneumoniae to mupirocin and human serum contributes to decreased serum susceptibility through a multifactorial process, and further investigation is needed to understand the impact on clinical outcomes in the human host.